Disentangling glial diversity in peripheral nerves at single-nuclei resolution

The peripheral nerve contains diverse cell types that support its proper function and maintenance. In this study, we analyzed multiple peripheral nerves using single-nuclei RNA sequencing, which allowed us to circumvent difficulties encountered in analyzing cells with complex morphologies via conventional single-cell methods. The resultant mouse peripheral nerve cell atlas highlights a diversity of cell types, including multiple subtypes of Schwann cells (SCs), immune cells and stromal cells. We identified a distinct myelinating SC subtype that expresses Cldn14, Adamtsl1 and Pmp2 and preferentially ensheathes motor axons. The number of these motor-associated Pmp2+ SCs is reduced in both an amyotrophic lateral sclerosis (ALS) SOD1G93A mouse model and human ALS nerve samples. Our findings reveal the diversity of SCs and other cell types in peripheral nerve and serve as a reference for future studies of nerve biology and disease. Using single-nuclei RNA sequencing to interrogate gene expression in peripheral nerves, Yim et al. reveal diverse glial subpopulations and identify a novel myelinating Schwann cell subtype that preferentially ensheathes motor axons and is depleted in ALS nerve samples from mouse models and patients.